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Restoring neurological and cognitive function in individuals who have suffered brain damage is one of the principal objectives of modern translational neuroscience. Electrical stimulation approaches, such as deep-brain stimulation, have achieved the most clinical success, but they ultimately may be limited by the computational capacity of the residual cerebral circuitry. An alternative strategy is brain substrate expansion, in which the computational capacity of the brain is augmented through the addition of new processing units and the reconstitution of network connectivity. This latter approach has been explored to some degree using both biological and electronic means but thus far has not demonstrated the ability to reestablish the function of large-scale neuronal networks. In this review, we contend that fulfilling the potential of brain substrate expansion will require a significant shift from current methods that emphasize direct manipulations of the brain (e.g., injections of cellular suspensions and the implantation of multi-electrode arrays) to the generation of more sophisticated neural tissues and neural-electric hybrids in vitro that are subsequently transplanted into the brain. Drawing from neural tissue engineering, stem cell biology, and neural interface technologies, this strategy makes greater use of the manifold techniques available in the laboratory to create biocompatible constructs that recapitulate brain architecture and thus are more easily recognized and utilized by brain networks.